title: Induction of P4504A activity improves pressure-natriuresis in Dahl S rats.
abstract: Clofibrate has been reported to prevent the development of hypertension in Dahl S rats, but its mechanism of action remains to be determined. The present study examined the effects of clofibrate on renal P4504A activity and the pressure natriuresis relationship in Dahl S rats. Dahl S and R rats fed a low-salt diet (0.4% NaCl) were given either clofibrate (240 mg/kg/d) or vehicle (20 mmol/L Na2CO3) in their drinking water for 1 week and then switched to a high salt diet (8% NaCl) while continuing drug treatment. After 3 weeks, mean arterial pressure in ketamine-Inactin anesthetized rats averaged 121+/-2 (n=8) in Dahl R, 173+/-8 (n=6) in Dahl S, and 139+/-4 mm Hg (n=7) in clofibrate-treated Dahl S rats. Increasing renal perfusion pressure (RPP) from 100 to 150 mm Hg in Dahl R rats increased sodium excretion (U(Na)V) from 2.9+/-0.7 to 9.7+/-3.2 micromol/min/g kwt. In contrast, the pressure natriuresis relation was blunted in Dahl S rats and U(Na)V only increased from 2.7+/-0.9 to 6.1+/-1.3 micromol/min/g kwt. The pressure natriuresis relation was improved in clofibrate-treated Dahl S rats and U(Na)V increased from 5.1+/-1.3 to 16.7+/-2.6 micromol/min/g kwt. At similar levels of RPP, the fractional excretion of sodium tended to be higher in clofibrate-treated than in vehicle-treated Dahl S rats, but not significantly. Glomerular filtration rate (GFR) was 40% higher in clofibrate- compared to vehicle-treated Dahl S rats (0.9+/-0.2 versus 0.6+/-0.2 mL/min/g kwt), and was not significantly different from the values seen in Dahl R rats (0.9+/-0.1 mL/min/g kwt). Clofibrate induced the expression of P4504A protein in the renal cortex and outer medulla of Dahl S rats. These data suggest that induction of renal P4504A activity with clofibrate improves the pressure natriuresis relation in Dahl S rats by primarily increasing GFR.
authors.affiliation: Department of Physiology, Medical College of Wisconsin, Milwaukee 53226-0509, USA.
authors.forename: M
authors.initials: M
authors.lastname: Alonso-Galicia
authors.forename: B
authors.initials: B
authors.lastname: Frohlich
authors.forename: R J
authors.initials: RJ
authors.lastname: Roman
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002994:Clofibrate / Q000494:pharmacology*; D042926:Cytochrome P-450 CYP4A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004039:Diet, Sodium-Restricted; D004790:Enzyme Induction; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D006973:Hypertension / Q000235:genetics / Q000517:prevention & control*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000096:biosynthesis; D007668:Kidney / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D007672:Kidney Cortex / Q000201:enzymology; D007679:Kidney Medulla / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000096:biosynthesis*; D009318:Natriuresis / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D012982:Sodium, Dietary
chemical_list: D000960:Hypolipidemic Agents; D007527:Isoenzymes; D012982:Sodium, Dietary; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A; D002994:Clofibrate